Our prior patent application PCT/SE88/00691, filed on Dec. 20, 1988, relates to a group of novel compounds which are useful in the treatment, acute as well as long term, of cardiac arrhythmias of diverse etiology. Among the compounds included in the group of compounds disclosed in said application is almokalant (p-INN), 4-[3-[ ethyl[3-(propylsulfinyl)propyl]amino]-2-hydroxypropoxy]benzonitrile having the formula ##STR2## which can be obtained as a stereoisomeric mixture as well as in the form of the different stereoisomers, for instance:
4-[3-[ethyl[3-(propylsulfinyl)propyl]amino]-2(R)-hydroxypropoxy]benzonitril e, PA0 4-[3-[ethyl[3-(propylsulfinyl)propyl]amino]-2(S)-hydroxypropoxy]benzonitril e.
The stereoisomeric mixture as well as the above mentioned pure stereoisomers can be obtained by oxidizing the appropriate 4-[3[ethyl[3-(propylthio)-propyl]amino]-2-hydroxy]benzonitrile with m-chloroperbenzoic acid or analogous to methods disclosed in the above mentioned prior patent application.
Almokalant in its free base form is an oil. It is a viscous, sticky substance, problematic to handle in the manufacture of solid dosage forms. It has a pronounced tendency to give a repellent odorous degradation product with a smell resembling old onions. No solid dosage forms containing the polystyrene sulphonate complex of almokalant have been reported. The polystyrenesulphonate complex of almokalant is described in the European patent application EP 90850242.0.
Several different ways were tested in order to prepare a solid dosage form of almokalant. Commonly used methods had the following disadvantages.
Due to the instability of the base and its tendency to worsen tablet binding properties, solid dosage forms of the free base are difficult to produce. See further reference example III.
Tablets prepared by conventional technique, with almokalant dissolved in an acidic granulating solution, have inferior stability properties and develop a repelling onion-like odor. See further reference examples I and III.
The use of complexes of drug substances with ion exchange resins in pharmaceutical formulation is described previously. A way to obtain a controlled release suspension containing codeine is described by Amsel L.P. et al. "Unique Oral Controlled Release Systems": In-Vivo Drug Release Pattern pp. 83-93 where a complex between codeine and an ion exchange resin is coated with a diffusion membrane and then formulated into a suspension. In addition, Pennwalt Corporation has published a series of patents describing the use of ion exchange resins having pharmacologically active substances absorbed thereon for use in controlled release preparations either as such or further coated with diffusion membranes (U.S. Pat. No. 4,221,778, EP 0171 528, EP 0 254 811). Other uses of ion exchange resin complexes with drugs in pharmaceutical formulation is for example summarized by Raghunathan et al. J Pharm Sci 1981, 70, (No. 4), 379-384.